Review Article

Schmutzhard, Multiple sclerosis and Lyme borreliosis

539
wiener klinische
wochenschrift
the middle european journal
of medicine

Wien Klin Wochenschr (2002) 114/1314: 539543

Springer-Verlag 2002

Printed in Austria

Multiple sclerosis and Lyme borreliosis

Erich Schmutzhard
Department of Neurology, University Hospital, Innsbruck, Austria

Summary. In a deductive approach the two disease

entities of multiple sclerosis and chronic progressive neuroborreliosis are discussed. Various clinical features, seroepidemiology, neuroimaging, CSF findings, CSF serology, specific proteins within the CSF and antibodies
against neuronal structures as well as the most recent
findings of different dendritic cells within the CSF are
discussed as a means of differentiating these two disease
entities.
Kew words: Neuroborreliosis, progressive borrelial
encephalomyelitis, multiple sclerosis.

Materials and methods

A thorough search in Pubmed and Medline libraries was
done using the two entry codes of multiple sclerosis and Lyme
borreliosis (or neuroborreliosis respectively): 60 entries were
found in which both terms were keywords of the publications.

Results
Ten topics were identified as being usable and helpful
in the deduction of the causative relationship between
these two diseases. They are listed in Table 1.

Seroepidemiology
Introduction
Multiple sclerosis is a relapsing/remitting or chronic/
progressive disease of presumably autoimmune origin affecting mainly or exclusively the CNS, leading to demyelinisation and remyelinisation. Many pathogenic agents
have been incriminated in being either directly involved in
the pathogenesis or indirectly, i.e. by triggering an autoimmune process within the CNS [50].
Gay and Dick were the first to discuss spirochetes as
the possible causative agents of multiple sclerosis [15],
and Kurtz et al. proposed both relapsing fever and Lyme
disease borreliae as having the capacity to cause a central
nervous system disease equal or similar to multiple sclerosis [24]. Although these medical hypotheses have never
been substantiated by biological, biochemical or molecular-biological findings, other authors have continued to
postulate a causative relationship between multiple sclerosis and spirochetes [4, 10, 15, 27].
The etiology of multiple sclerosis is still a subject of
controversial discussion and it continues to cause considerable uncertainty in the medical community, reflected by
a very recent Polish publication in which a causal relationship between the agent of Lyme borreliosis and multiple
sclerosis is postulated [5].
We aim here to clarify this confusion within the medical community by contrasting epidemiologic, clinical and
diagnostic findings of neuroborreliosis, and in particular
chronic neuroborreliosis, with multiple sclerosis. In addition we discuss the most recent developments in molecular biology and neuroimmunology with respect to these
two diseases. Using deductive methods we believe we
have achieved conclusive results, i. e. we hope to clarify
the relationship between these two diseases.

Whereas several authors [4, 10, 15, 24, 27] suggested

a hypothetical causal link between Lyme disease and multiple sclerosis on epidemiologic grounds, Schmutzhard
et al. [40, 42, 43] and Coyle [6] clearly showed, both in
controlled studies and in a series of consecutive patients,
that MS patients had positive serology in serum less frequently when compared with well matched control persons. However the frequency of recalled tick bites and the
frequency of potential tick exposure (frequenting grassland, edges of woods etc.) was significantly higher in
control patients compared with multiple sclerosis patients
[43]. Only 1/50 of MS patients had an intrathecal production of borrelia antibodies [42], and because this study
was done in the mid-eighties it cannot now be determined
whether the specific Borrelia burgdorferi IgG antibodies
were produced intrathecally or if they merely reflected the
disruption of the blood brain barrier.
Table 1
Seroepidemiology
Clinical presentation
Neuroimaging
Cerebrospinal fluid
CSF serology
Kynurenines
Matrix metalloproteinases
Cross reactivity of B. burgdorferi and myelin basic protein
specific antibodies
Dendritic cells
Molecular mimicry

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Schmutzhard, Multiple sclerosis and Lyme borreliosis

These studies [6, 4043] were accepted as clearly

indicating that, on seroepidemiologic grounds, a causative
link between multiple sclerosis and any form of Lyme
borreliosis was not to be suspected. However, only recently, Chmielewska-Badora performed another seroepidemiologic study comparing the serology of 26 MS patients
with 743 rather poorly defined non MS patients [5].
Whereas in our study [43] 14,2% of the MS patients,
compared with 25,2% of the very well matched (age, sex
and ecologic exposure) controls were seropositive (103
patients in each group), the rather unbalanced study of
Chmielevska-Badora showed 10/26 MS patients (38,5%)
being seropositive compared with 145/773 (19,4%) of
non MS patients. The authors do not elaborate on the
frequency of tick bites, exposure to tick-infested environment, or age and sex matching. However, despite this
recent finding seroepidemiology clearly indicates that the
relationship between MS and the presence of anti-Borrelia
burgdorferi antibodies is highly unlikely to be causal.

Clinical presentation of multiple sclerosis and

the various forms of neuroborreliosis
There is little doubt about the clinico-neurological
presentation of MS with either a relapsing/remitting
course of disease or a chronic/progressive form [39, 50].
It is only the latter that in a very rare instance could
be mistaken for a progressive borrelial encephalomyelitis
[2, 13, 18, 44, 53]. Whereas the progressive form of MS in
most instances is confined to a chronic myelitis, with
frequent relapses and remittances in the early days of
disease before finally becoming progressive [13, 50], the
progressive borrelial encephalomyelitis, as defined by
Ackermann et al. [2], begins with a progressive (chronic)
myelitic disease [18]. In contrast to progressive borrelial
encephalomyelitis, early neuroborreliosis, as seen in
Bannwarths syndrome includes the clinical entities of
meningitis, radiculoneuritis and peripheral polyneuritis
cranialis [30, 39]. None of these 3 syndromes is ever seen
in MS. In recent years neuroophthalmic manifestations of
Lyme disease have been discussed [3, 29, 38], however
both the oculomotor presentations and manifestations involving the optic nerve are clearly different in MS, presenting either as optic neuritis or as a pontomesencephalic
nuclear lesion of the oculomotor system leading to double
vision [50]. In contrast, Rothermel et al. [38] and Balcer
et al. [29], describing neuroophthalmic manifestations of
Lyme disease, saw in children either peripheral oculomotor disturbances or compression of the optic nerves. Gold
et al. (1990), Lyon-Caen et al. (1994) and Karussis et al.
(1999) published, rather outspokenly, clear guidelines to
delineate the two disease entities of MS and Lyme borreliosis [16, 23, 26].

Neuroimaging
No larger series has been published on the neuroimaging presentation of either acute or chronic neuroborreliosis. Nevertheless both cranial computertomography (cCT)
and magnetic resonance tomography (MRT) have been
performed on children and adults with neurological Lyme
disease [11]. Demaerel et al. described ring enhancing
lesions as one possible MRT-feature [8]. This finding

added to differential diagnostic confusion as patchy areas,

not localized periventricularly, were previously thought to
be more frequently seen in patients with chronic neuroborreliosis i. e. progressive borrelial encephalomyelitis. In
MS-patients a typical periventricular distribution pattern
is regularly found. In addition to the size of the hyperintense lesions seen on T2 weighted images, their distribution is a further, possible way of distinguishing multiple
sclerosis from chronic borrelial encephalomyelitis [50]. It
must be stressed that the study on the 3 cases of neuroborreliosis, appearing similar to multiple sclerosis on MRT,
was performed on children. Since it never has been repeated in adults, this finding might be a feature seen only in
young neuroborreliosis patients. As early as 1990, Egerter
et al. were able to show that central nervous system borreliosis is clearly mirrored by MRT pathology [11]. However, it was not until 1998 that Triulzi and Scotti published
an MRT algorithm with which they were able to differentiate various diseases from multiple sclerosis [48]. In addition to conventional MR images (T1 and T2 weighted
images) they used the FLAIR technique, which adds only
little to differential diagnostic accuracy; however, when
they calculated the magnetisation transfer ratio (MT ratio)
they were able to provide a useful tool for the characterization of both multiple sclerosis and other white matter
diseases such as vasculitis and chronic neuroborreliosis as
well as acute disseminated encephalomyelitis (ADEM)
[39, 50]. When employing additional imaging techniques
such as diffusion and perfusion weighted MR, further
differentiation from chronic borrelial encephalomyelitis
and vasculitis is easily possible [39, 50]. Thus, by means
of neuroimaging, i. e. various magnetic resonance techniques, the appropriate differentiation of several diseases,
including multiple sclerosis, from chronic progressive
neuroborreliosis seems to be possible, and obviously
easier in the appropriate clinical / neurological setting.

Cerebrospinal fluid findings

Pohl et al. described the cerebrospinal fluid findings
in various neurological manifestations of Lyme disease
[33], Schmutzhard et al. adding CSF characteristics in
chronic neuroborreliosis [41]. It is mainly the plasmacellular pleocytosis, increased intrathecal production of IgG,
IgM and in most instances IgA which give the first
indication of a possible borrelial origin of the neurological
infectious / inflammatory disease. Typically, the range of
CSF glucose is within normal limits, but CSF protein is
highly elevated. Differing from other infections of the
CNS, plasmacellular pleocytosis is seen in the early phase
of the disease and does not subside over a prolonged
period of time (at least 6 months, own observation). In
almost all acute and subacute infectious diseases of the
nervous system intrathecal IgM and IgG production can
be observed. In contrast to this, intrathecal IgA production, demonstrated by a positive IgA index [35], is rarely
seen in purely infectious diseases. However, in autoimmune disease, and in [or such as?] acute transverse
myelitis, acute disseminated encephalomyelitis (ADEM)
or acute hemorrhage leukoencephalitis (Hurst) such an
intrathecal IgA production can be observed [39, 50]. Neuroborreliosis is one of very few infectious diseases of the

Schmutzhard, Multiple sclerosis and Lyme borreliosis

nervous system in which from the early stage of disease

onwards throughout the prolonged course of chronic manifestations, i. e. progressive borrelial encephalomyelitis,
intrathecal IgA production may continue to be observed
[39]. It seems justified to add the constellation of a pathological/inflammatory CSF finding with mainly plasmacellular pleocytosis and intrathecal IgM, IgG and IgA
production to the list of typical diagnostic features in
neuroborreliosis, including chronic neuroborreliosis. Both
plasmacellular pleocytosis and intrathecal IgA production
are virtually never seen in patients with multiple sclerosis.
On the other hand a patient with chronic neuroborreliosis
being clinically similar to multiple sclerosis virtually
never shows the typical MS pattern in his / her CSF, i. e. no
pleocytosis (or very low pleocytosis < 15/mm3) with isolated intrathecal IgG production (no intrathecal IgM production).

CSF serology
It is well accepted that intrathecal production of specific Borrelia burgdorferi antibodies is one of the hallmarks of diagnosis of neurological Lyme disease. Only
rarely is a negative Lyme serology seen in acute neuroborreliosis patients, and is most likely to be found in
acute neuroborreliosis patients who had have early antibiotic treatment [39]. In chronic neuroborreliosis the intrathecal production of borrelia-specific IgG, IgM (and IgA)
antibodies is typical. Since polyclonal stimulation may
cause a mild increase of various nonspecific antibodies,
including Borrelia burgdorferi antibodies (IgG), commercially available tests may yield positive results. This aspect has been addressed and discussed at length by Coyle
et al. [7] and Lana Peixoto [25], finally reaching the
conclusion that in MS patients a reactive Lyme serology
might test positive. However, this represents the breakdown of the blood brain barrier and never indicates an
autochthonous intrathecal production of specific Borrelia
burgdorferi antibodies [19]. Various methods of identifying intrathecal (autochthonous) production of specific
Borrelia burgdorferi antibodies have been employed, such
as the equilibration of CSF and serum (to bring the albumin levels to equal concentrations by means of diluting
the serum appropriately) or the detection of specific oligoclonal bands within the CSF by CSF electrophoresis.
These methods are extremely helpful in diagnosing chronic neuroborreliosis and differentiating it from multiple
sclerosis [20, 41]. Within the correct clinico-neurological
setting, Lyme serology should be an appropriate method
of differentiating the two diseases of multiple sclerosis
and chronic / progressive neuroborreliosis. This is particularly important since antibodies for neuronal proteins have
been thought to exist in patients with neuroborreliosis,
although the pathogenic relevance of these was never
clearly determined [22]. As in any other progressive
disease of the central nervous system finally leading to
destruction of neuronal cells, it is conceivable that also in
patients with neuroborreliosis antibodies to neuronal proteins released from degenerating neuronal cells are eventually formed. Therefore, the specificity of such antibodies against neuronal proteins clearly needs to be elucidated and validated, particularly with respect to the time

541

course of a subacute or chronic inflammatory disease of

the nervous system.

Cross-reactivity of Borrelia burgdorferi and

myelin basic protein specific antibodies
As outlined above, antibodies against neuronal proteins have been shown to exist in patients with both
multiple sclerosis and neuroborreliosis [22, 47]. In the
latter, myelin basic protein specific antibodies have been
found and have been considered to be specific for multiple
sclerosis [47, 50]. Pohl-Koppe et al. did not find crossreactivity of intrathecal antibodies to Borrelia burgdorferi
and myelin basic protein [34]. This means that the detection of myelin basic protein-specific antibodies might be
an additional means of differentiating multiple sclerosis
from chronic / progressive neuroborreliosis. In addition to
antibodies against myelin basic protein, typically found in
multiple sclerosis, antibodies against oligodendrocytic
glycoprotein have also been found to be present in the
CSF of MS patients [36]. In a comparative study these
antibodies (against oligodendrocytic-glycoprotein) could
not be found at a comparable level in neuroborreliosis
patients when compared with MS patients [36]. This,
therefore, justifies the assumption that antibodies against
both myelin oligodendrocytic-glycoprotein and myelin
basic protein may exist at a low level in all patients in
whom neuronal cells degenerate, either by necrosis or
apoptosis, but they are typically seen at higher levels
in patients with multiple sclerosis. However, it has to be
accepted that a clearcut discrimination of the two diseases,
multiple sclerosis and progressive borrelial encephalomyelitis, by measuring the levels of antibodies against
myelin-oligodendrocytic-glycoprotein and / or myelin basic protein is not easily possible.

Kynurenines and matrix metalloproteinases

in CSF
Neuroactive kynurenines have been shown to occur in
CSF in both the acute and chronic forms of neuroborreliosis [14, 17]. These kynurenines, reflecting excitotoxicity,
have never been shown to be upregulated in multiple
sclerosis.
Matrix metalloproteinases have been shown to be
induced by Borrelia burgdorferi in neural cultures [32].
Very recently these molecules have been implicated in the
pathogenesis of multiple sclerosis [12]. Their suggested
role includes the disruption of the blood brain barrier,
immune cell transmigration into the central nervous system and myelin degradation. Therefore, these molecules
can be detected in virtually all inflammatory diseases
leading finally to neuronal cell degradation [12]. However,
Yushschenko et al. could clearly show that certain matrix
metalloproteinases (e.g. MMP-9) are strongly correlated
to the CSF cell count [54]. Very recently, Galboiz et al.
showed that MMP 9 levels were not different in the CSF
of patients with multiple sclerosis and in healthy controls
[12]. However, elevated levels of MMP-7 and MT1-MMP
were detected.
To our knowledge, no prospective study has addressed the issue of using various matrix metalloproteinases and / or their respective tissue inhibitors to differenti-

542

Schmutzhard, Multiple sclerosis and Lyme borreliosis

ate the two disease entities of multiple sclerosis and progressive borrelial encephalomyelitis.

Molecular mimicry
Molecular mimicry is the concept that antigenic determinants of micro-organisms resemble antigenic determinants of the host. It is frequently cited as a plausible
mechanism to account for the association of infections
and autoimmune disease [49, 53].
The currently controversial issue of molecular mimicry in Lyme borreliosis might definitely be an important
issue in chronic neuroborreliosis [1, 21, 28], although
Rose and Mackay looked critically at various human diseases and the role of molecular mimicry [37]. They concluded that, based on analogous sequences of aminoacids
or on cross-reactions of monoclonal antibodies, numerous
examples of molecular mimicry have been reported, but to
date there has been no clear example of a human disease
caused exclusively by molecular mimicry [37]. In view of
recent findings in Lyme arthritis, where molecular mimicry was demonstrated at the single cell level [49], the
statement by Rose and Mackay [37] must at least be
reconsidered.

Dendritic cells
Steinman et al. [46] and Dittel et al. [9] stipulated that
dendritic cells may be crucial in inducing and regulating
immune responses not only against pathogens but also
against autoantigens. Very recently, this issue was addressed by Pashenkov et al. who found two subsets of
dendritic cells within the human cerebrospinal fluid [31].
Whereas myeloid dendritic cells, one of the two subsets,
were found to be elevated in various neuroinflammatory
conditions including MS, optic neuritis, and to some extent also in septic meningoencephalitis and neuroborreliosis, the other subset of dendritic cells the plasmacytoids
were found to be significantly elevated in the CSF of
Lyme neuroborreliosis compared with other neuroinflammatory conditions. The initially elevated number of dendritic cells in the CSF drops dramatically over a few
weeks in acute neuroborreliosis and appropriate antimicrobial chemotherapy.

Conclusion
From this approach of deductive argumentation it is
without doubt that acute neuroborreliosis is a clearly distinct disease entity. Similarly without doubt is the fact that
any form of chronic neuroborreliosis, e. g. progressive
borrelial encephalomyelitis, may present as an MS-like
disease; however, there are many ways to clearly differentiate multiple sclerosis from any form of chronic neuroborreliosis. It is not the task of this deductive outline to
discuss either the treatment protocols for the various
forms of multiple sclerosis or the distinct treatment protocol for neuroborreliosis (the reader is referred to the published practice guidelines for the treatment of Lyme disease by Wormser et al. [52] and Steere et al. [45]).
Since both treatment options and prognosis are different in these two disease entities (multiple sclerosis and
chronic neuroborreliosis) it is necessary to distinguish
them as early as possible and with maximum possible

certainty, keeping in mind the treatment options and their

prognostic aspects.
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Correspondence: Prof. Dr. Erich Schmutzhard, Universittsklinik fr Neurologie Innsbruck, Anichstrasse 35, A-6020
Innsbruck, Austria, E-mail: erich.schmutzhard@uibk.ac.at